Sunday, November 22, 2009

It’s possible that twelve years of working as a programmer in the online publishing industry has sharpened my interest in open access, the idea that the public should have unlimited access to all scholarly publications. PLoS recently published "University Public-Access Mandates Are Good for Science," in which the author argues that, among other things, public access will help lift the “veil” from faculty research, creating greater public interest in (and funding for) research.

Open access is good for everyone who participates in research, really, except for the publishers. Current publication models based on fee for access, subscription or pay per view, aren’t compatible with open access. They might be compatible with a delayed access model, in which new content is embargoed for a year or so, then released to the public, and some people advocate those models. Others advocate the use of government funds to provide the services currently provided by the publishing industry.

What’s the publishing industry currently providing, and funding by charging for access to articles? Peer review is a service often mentioned, and it is extremely important. If a paper were published without having been reviewed by its author’s peers, no one would have any good way of judging its value. Loss of peer review might lead to chaos and the inability to find the wheat in the chaff. However, I am not convinced that this service can really be said to be provided by the publishing industry. The peers who review are, by definition, other researchers in the same community as the author of a submitted paper. Reviewers provide their services to a particular journal for free, as a resumé building move, to get a chance to see the very newest research before anyone else, and possibly out of the goodness of their hearts, to give back to the community. Would they be equally willing to donate their time to a well-known non-profit or university-affiliated group which organized review services, rather than a for-profit publishing group? I don’t see why not.

Indexing is also important. If a paper is no longer archived on a journal’s web site, but instead at a university’s institutional repository, would readers need to know the researcher’s university affiliation in order to find the paper? Readers could continue to use indexing services such as PubMed or Google Scholar, just as they do today. When presented with the title of an interesting article, my first step in finding the article’s text is never to try to find the journal’s site. I always visit Google Scholar first and let it show me my various options.

Journals are certainly useful for discovery purposes. I use Google Scholar to search for answers to specific questions, but I don’t use it to keep track of current research in a particular area. For that, I follow the latest articles published in particular journals, such as JAVMA or Applied Animal Behaviour Science. Certainly non-profit entities could serve similar purposes, aggregating links to important new recent articles. Authors might submit articles to these entities, just as they currently submit articles to journals.

The journal which publishes your article has a significant effect on how your article is perceived. If your article was accepted by the prestigious journal Nature, its importance will be perceived by readers to be greater than if the only journal you could find to accept it was some dinky little publication no one’s ever heard of. Again, non-profit entities could fill this purpose, but there would be some necessary lead time as some of them became established as high quality and others as, well, not so much.

What I haven’t seen mentioned as a useful contribution by the publishing industry is production editing — correction of spelling mistakes, bad grammar, and typos; modification of the paper’s layout to make it easier to read; conversion to PDF. I’m not sure if this is an important contribution in scholarly publishing or not. The articles I read seem to have more than their fair share of typos and grammatical mistakes compared to published books; it seems that in this area, content is valued much more highly than form. Perhaps this sort of work is something society would be willing to see lost.

This is all somewhat theoretical stuff at this point. Articles are being published open access (for example, in PLoS, the Public Library of Science), and indexing engines are indexing them. But the non-profit entities that I’m envisioning don’t seem to be springing up, and scholarly communities are still extremely dependent on publishing companies; the majority of articles are published in traditional for-pay journals. As a result, the goal of 100% release of scholarly articles under open access still feels somewhat distant. Some institutions are requiring their faculty to archive all publications in an open access institutional repositories; Harvard's new open access mandate is the most famous of these mandates. However, these institutional repositories have been described as “roach motels”: information goes in and doesn’t come out, due to poor searching facilities and lack of adherence to standards. (See “Institutional Repositories: thinking beyond the box.”) One previous comment on this blog mentioned arXiv, a highly successful open access repository in some of the hard sciences, but arXiv does not provide peer review services. A lot of the pieces of the puzzle exist, but they have not all been put together in a coherent way.

How can we organize the scholarly publishing community, which in fact consists of a huge number of communities in varied fields with their own publishing traditions? I’m glad it’s not my job to find the answer to that question. I suspect the answer will appear in its own time, and until then, I’ll keep following the various debates about open access, waiting to see what happens.

Saturday, November 21, 2009

Monday through Thursday evenings around five pm, I drive in to my school’s small animal hospital to collect spit from dogs. I’ve learned a lot about how to get spit out of a dog. It helps to have the right tools. If your subject is an adult human, you can ask them to drool into a cup. (Don’t actually spit! The manual doesn’t say why, but when I tried it, my spit contained long mucin strands which made it difficult to pipette up into a vial for storage.) If your subject doesn’t speak the same language as you do — mine don’t — or is otherwise recalcitrant, you might extract the spit with a small cotton rope. However, a new tool is now on the market: the Sorbette, a small sponge on a stick available from Salimetrics. (My endocrinology professor, upon hearing about Salimetrics, said: “An entire company dedicated to saliva? Who knew?”) Oh, wait. The Sorbette isn't actually all that new as technology goes: it turns out to just be an eye sponge. Not knowing much about eyes, I presume it is for adding things to or taking things away from them. But it's now also marketed to us spit collectors.

Salimetrics tells me to insert two Sorbettes under my subject's tongue and hold them there for a full minute. I should not swab. I did try this a few times. My subjects inevitably act like I have stuck a hot poker under their tongues, rolling their eyes and chewing madly. No Sorbettes have been damaged in this process, but it was only a matter of time. Also, the amount of saliva I actually acquired was too low for the assay I intended to perform on it.

So now I stick three Sorbettes in the side of the dog's mouth; this bothers them less, even with the greater mass. There also seems to be a fair amount of spit accumulating in the forward lower part of the dog’s mouth, between the outer edge of his teeth and inside his lip. And I do swab. The collection manual, when consulted, explained that swabbing is bad because it means you'll collect saliva from various different salivary glands, and so the levels of whatever you're testing might vary based on how much spit you get from which gland. This is a more important consideration for some other substances than for cortisol, which is what I care about.

Even so, the quantities of spit still occasionally leave something to be desired. My suspicion is that anxious dogs — which my study dogs are; that’s the point — just make less saliva than calm dogs, because their sympathetic nervous system is activated and telling them that making things which are useful for the process of digestion is not appropriate at this time. Eat later, worry about being stuck in the hospital now. In order to turn on the rest-and-digest parasympathetic nervous system, I have attempted waving treats under my subjects’ noses. Well, I’ve tried this once so far, and I did get a nice large sample that night. I left the treat behind with the dog; he was too anxious at the moment to ingest it, but I have hopes that he came around in my absence.

Once I have my sample, I balance it on a plate of ice and carry it upstairs to the clinical sciences laboratory, where I centrifuge it (3250 rpm, 15 minutes) so that it spins its way out of the sponge and into the tapered bottom of its vial. I then pipette it into a cryovial and secrete it in a -80° freezer. Done! When I have enough samples, I’ll perform an ELISA assay on them to find out how much cortisol is in each. I imagine I’ll report on that in detail here.

Saturday, November 14, 2009

After reading a post about how Strunk & White is a deeply weird book, I was inspired to pick it up and read it cover-to-cover, which I don't believe I'd ever actually done before. The book exhorts the reader, among many other wise statements, "Do not overstate":

When you overstate, the reader will be instantly on guard, and everything that has preceded your overstatement as well as everything that follows it will be suspect in his mind because he has lost confidence in your judgment or your poise.

I was briefly tempted to add this sentence to my email signature. It is the sentiment I would most like to convey to people who say things on the Internet. Too often, I read posts from people with whom I actually agree, but who make me flinch by overstating their case and poisoning the rest of their argument as a result. Certainly vet school has drilled into my head the rule that I should never make a statement that I can't back up, but even people who don't have graduate-level scientific training should be able to recognize that it's just bad debate style to make statements that overstep themselves. Less is more.

Thursday, November 12, 2009

Today, a newspaper local to me published a story about the devocalization debate in Massachusetts. The Massachusetts legislature is currently considering a bill which would make illegal the procedure for debarking dogs, or surgically altering their vocal cords to reduce the noise they make when barking. Various humane societies (including MSPCA-Angell) support the bill, because they feel that debarking is inhumane. The Massachusetts Veterinary Medical Association opposes the bill, because it takes away from veterinarians the ability to exercise their professional judgement.

I can see both sides of the issue. I don't know any details about the procedure itself, but I do know that when a dog barks excessively, there is usually some reason for it. Dealing with the symptom (barking) and not the underlying problem (separation anxiety, boredom, possibly something else) is not going to serve the owner or the dog well in the long run. The problem will manifest some other way. I don't know if this procedure is being used frequently and inappropriately in Massachusetts; I don't personally know any veterinarians who would perform it lightly, but I imagine that some such do exist in the state.

But should it be made illegal? I have to agree with the MVMA that the state should not be telling veterinarians how to do their jobs. Extenuating circumstances do occur, and I believe the decision to perform a procedure like this should be in the hands of the individual who spent four years earning his DVM (plus possible post-doctorate work in a residency program), and the owner of the dog, not in the hands of lawmakers who don't know the individual situation. Under the proposed bill, veterinarians will be able to apply for exemptions for "medical reasons," and only time would tell if behavior became recognized as a medical reason. But I don't like the idea of having to apply to the state to have a medical procedure done. I don't like the direction that takes us.

What do I propose as a solution? I think this problem should be solved by veterinarians. I think the MVMA should recognize that the problem is one that the citizens of this state currently find important, and should treat it seriously. A good first step could be forming a task force composed of representatives of the MVMA and of the groups who are in favor of this bill. This task force could provide a report on how often the debarking procedure is actually being performed, and under what circumstances. The task force could then identify problematic cases and discuss how they should have been handled differently, then discuss what options should have been available to that veterinarian and owner in that case. Are a significant number of veterinarians jumping to the surgery too quickly? Perhaps the MVMA can provide education to its members about the consequences of this procedure and some alternatives. Was the owner unaware of behavioral interventions? Could he not afford a trainer or a dog walker? Perhaps options should be made available for low-income people who cannot afford to deal with their animals' behavioral problems.

I would trust the MVMA and the MSCPA to find a solution to this problem, if they were able to work together. I'm not sure I trust the Massachusetts legislature to do so.

Tuesday, November 10, 2009

A researcher does a study. Based on the results, he comes to a conclusion about a small part of the nature of the universe. He writes up this conclusion and sends it to a journal. His peers review it and conclude that he did a good job in designing, implementing, and interpreting his study. In due time, his paper is published. The researcher receives non-monetary rewards.

Then, one day, he realizes he was wrong. He was wrong in a small way; he doesn't have to do another study to disprove his results, but he realizes he leapt to his conclusions. His interpretation was faulty. His data would have appeared different under very slightly changed study design. He considers letting his colleagues know. But how? He can't amend his paper. It is out there, as unrecallable as toothpaste from a tube. Does he write a letter to the journal? Post a note on his web page? Perhaps blog? None of these things will reach the audience that his original paper did.

It struck me, recently, how clumsy the communication protocol is that researchers use. They publish in papers. For a paper to change after publication, a slow, complicated machinery must be put in motion. A subsequent paper can show conflicting results. The paper can be found to be based on fraudulent data and recalled. Or the results can simply be gradually forgotten as science moves in a different direction. In any of these situations, change is slow.

I said as much in my bioethics class today. The professor asked, "How would you change things?" I suggested a world in which peer reviewed papers still existed, but another, non-peer-reviewed channel existed as well. We'd all know to take this channel's contents with a grain of salt, as they would be offered without the cautious filter of peer review. We would be much less likely to reference data from this channel in our papers. But we'd keep abreast of the conversations in it before completely trusting information we found in the more respectable peer-reviewed channel. It would be a place for back-and-forth, for something closer to a true conversation. (I've seen conversations in journals: two labs publishing an alternating series of articles that reference and refute each other, a dialog conducted over the course of years. It's rare and somewhat awestriking to observe.)

One of my classmates replied that I was idealistic. Well, sure. But this second channel is technologically very possible today. It might even currently be in the midst of developing out of the medium of science blogging. What would it take to start building mechanisms for allowing people to search it as easily as they currently use PubMed and Google Scholar to search the primary channel? I can't yet think where to start. Maybe all I need to do is sit back and wait, and watch the scientific information communication protocol evolve on its own, from its current clumsy elephantine form to something more nuanced and potentially graceful.

My roommate, RKt, has a 55 gallon marine fish tank. It is awesome. For more than a year, a small yellow fish has lived in it. I never saw this one, unlike the other fish; I'd forgotten he was even in there. He hides all the time. RKt, who interacts with the tank much more than I do, reports that she sees him about once every three months. He does not even come out at feeding time for delicious brine shrimp.

Last week, RKt brought home a new small yellow fish, of the same species, from a friend's tank which is being broken down. This new fish is very bold. He perches in high, easy to see places, on top of corals. He swims around fearlessly in open water. They have completely different personalities.

I remember our series of fire fish, little red and white gobies. I liked our first one so much that when he died I bought a second for the tank, and a third after that. (I have since given up, as they seem to have bad luck.) Firefish #2 (named S.S. Goby for his trait of rising up out of nowhere like a surfacing submarine) was best of friends with our burrowing shrimp. They shared what must have been a complex burrow structure under the live rock, living as congenial roommates. Firefish #3 (Mr. Goby) did not have much to do with the shrimp and liked to find other hiding places.

I'm intentionally anthropomorphizing, here, for amusement value. But it is clearly true to me that fish of the same species can behave in very different ways. That, to me, is personality.

Monday, November 9, 2009

Last week in journal club I presented "Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses," by Oberlander et al., published in Epigenetics in 2008. This paper tries to get at one small part of the mechanism for how the in utero experience can affect a fetus, possibly even affecting the baby's personality.

Oberlander's study builds on earlier work done in rats. Researchers found that the offspring of particular rat dams were less fearful than average. Specifically, these rat moms were spending extra time licking and grooming their babies, and performing "arched-back nursing." They were dubbed "LG-ABN" dams (licking grooming, arched-back nursing.) Their babies acted less fearful in stressful situations, and had a blunted stress response on the HPA axis.

The HPA axis... This is in large part what I'm studying for my Masters project, so it's hard to limit myself to a short explanation of what it is. In short, one way in which one's brain (or part of it: the hypothalamus, the H in HPA) responds to stress is to send a message to the pituitary (P), which in turns sends a message to the adrenals (A). The adrenals release cortisol, which is known as the stress hormone. Cortisol is what researchers look for in your blood if they want to quantify how stressed you are. Stress out two animals, check their cortisol levels, conclude that the one with higher levels reacted more strongly to the stimulus — that's the formula for any number of experiments, including this one. (It is, as always with physiology, more complicated than that, but the idea that there's a correlation between increased cortisol levels and increased stress is a good start.)

So these babies of LG-ABN moms had a smaller cortisol spike in response to stress. Further work elucidated part of why that happened: the receptors to which cortisol binds in the brain send a message back to the top of the HPA to tell it to stop releasing cortisol ("that's enough, there's plenty out here!") in a negative feedback loop. These receptors (glucocorticoid receptors, abbreviated "GR") were in excessive supply in the brains of these less fearful rats, so the negative feedback loop worked well, and the rats' brains responded to rising cortisol levels by releasing less cortisol — with the result that the spike of cortisol was smaller in response to a stressful stimulus.

Meanwhile, the researchers also found that this trait of decreased fearfulness was not genetic in the normal sense. If they fostered baby rats from non-LG-ABN dams on LG-ABN dams, these babies who were not genetically related to the LG-ABN mom grew up to be less fearful, presumably simply by being raised by her. And they passed the trait on to their offspring! It turned out that the trait was being passed along epigenetically. We all learned in elementary school about genetic traits — getting brown eyes because you got brown eye genes from mom and dad. And we all know that genes are coded on DNA. Epigenetic changes involve not different genes, but changes to the higher-level structure of the DNA. Instead of involving changing the building blocks of the DNA (the genes), epigenetics involve changing the shape of the building, or sometimes tacking something new on to the outside of it.

In this case, it turned out that in order for GR to be produced (remember that receptor for cortisol, necessary for negative feedback?), the machinery for reading genes had to have free access to the GR gene itself. However, an area of that gene had become methylated — in other words, another object was sitting on it, blocking access. The machinery for reading genes couldn't read that gene as well, so fewer GRs were made. Fewer GRs meant less negative feedback and a more easily stressed baby rat.

That's all background. Oberlander, who wrote the paper I presented, wondered whether the same mechanism applied to humans. He knew that human mothers who are depressed during pregnancy often give birth to babies with more reactive HPA axes. Could that be because those babies had fewer GRs, as a result of methylation of the GR gene? He also wondered about the effects of SRI medication, such as Prozac, on this system.

82 pregnant women were enrolled in this study. 33 were taking SRI medication. All were tested using a scale for depression, which resulted in a numeric score; higher scores implied greater depression. Blood was drawn from the moms in their second and third trimesters, and when they gave birth. Blood was taken from the babies' umbilical cords at birth. Then the babies were tested at three months of age for their response to a mild stressor.

The researchers found that the babies of depressed moms did tend to have increased methylation of the GR gene, exactly in the spot that they expected. That increased methylation correlated with an increased cortisol spike when the babies were mildly stressed. SRI exposure in utero didn't have any effect on the size of the spike, although babies whose moms were medicated did tend to have lower cortisol levels in general.

This paper spoke to me on two levels. I enjoy reading about mechanisms; I like imagining how all these little machines in our bodies interact to form our personality and affect how we experience the world. I also liked the study's methods, because I'm interested in finding ways of learning about living individuals. I want to study dogs, so I want to find ways of looking into their brains figuratively, not literally. Examining changes in DNA extracted from a blood draw is cool — it's something I could potentially do to someone's pet, perhaps as part of a study aimed at understanding why some dogs are more easily stressed to the point of biting than are others.

I think that the people who attended journal club found the paper interesting. Two professors who were in attendance work in this area of genetics and behavior, and had useful input for me. One pointed out that the list of variables that the paper's authors checked for in the pregnant women was very small. (It consisted of things like age, whether this was a first pregnancy, whether the pregnancy ended in C-section, whether the woman smoked or drank.) She listed some other things she would have checked for, such as body weight (fat can apparently produce cortisol). She also noted that the baby's blood sample came from umbilical cord blood, which is actually a mix of infant and maternal blood. Also, different parenting strategies weren't taken into account — did depressed mothers treat their babies differently in some way? She concluded that we'd all like to be able to see useful DNA changes just by taking blood samples (which is precisely one of the things that drew me to this paper), but it's actually very hard to do so, so this paper's results should be taken very cautiously.

Saturday, November 7, 2009

I figure the first thing I say on this blog should be a basic orientation to who I am and where I'm coming from. I'm a veterinary and graduate student at Tufts Cummings School of Veterinary Medicine. I say both "veterinary and graduate" because I'm in a dual-degree program: I spent two years working on my DVM degree; this year I'm working on my MS degree in Comparative Biomedical Science; and in the fall of 2010, I'll return to the DVM program for its final two years.

My graduate work is in stress in hospitalized dogs: can we develop behavioral tools for helping us tell how stressed they are? And once we've done that, are there ways of making them less stressed?

What I really want to study, though, is dog brains — well, dog minds, since I like them operating more than I like them preserved. I feel very lucky to have managed to find a way to spend a year studying domestic dogs at all. When I came back to school after 12 years working in online publishing, veterinarians told me they only studied sick dogs, and researchers told me they only studied wild animals. So it's been hard to find a way to straddle that border — to study the normal, healthy behavior of a domesticated animal. (It sounds fairly wild in my house during Middle Aged Golden Retriever Wrestling Hour every night, with snarls, barks, and body slamming, but I guess that doesn't count as the opposite of domesticated.)

It's hard to say what this blog will become, but one of the things that seems to be lacking in veterinary medicine and scientific research is good communication with people operating in other walks of life. The new culture of science blogging is trying to overcome that division, so I'm throwing my cap into that fray.

About the Dog Zombie

Jessica Perry Hekman, DVM, PhD is fascinated by dog brains. She is a postdoctoral associate at the Broad Institute of MIT and Harvard, where she studies the genetics of dog behavior. Her interests include the stress response in mammals, canine behavior, canine domestication, shelter medicine, animal welfare, and open access publishing. You may learn more about Jessica at www.dogzombie.com, or email her at jph at dogzombie dot com. All opinions expressed here are her own.

For the animal shall not be measured by man… They are not brethren, they are not underlings: they are other nations, caught with ourselves in the net of life and time, fellow prisoners of the splendor and travail of the earth. (Henry Beston)